IT9021063A1 - SYNTHESIS OF 1H, 3H-THIAZOL 3, 4-A BENZIMIDAZOLS 1-REPLACED ANTI-HIV ACTIVITIES - Google Patents
SYNTHESIS OF 1H, 3H-THIAZOL 3, 4-A BENZIMIDAZOLS 1-REPLACED ANTI-HIV ACTIVITIES Download PDFInfo
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- IT9021063A1 IT9021063A1 IT021063A IT2106390A IT9021063A1 IT 9021063 A1 IT9021063 A1 IT 9021063A1 IT 021063 A IT021063 A IT 021063A IT 2106390 A IT2106390 A IT 2106390A IT 9021063 A1 IT9021063 A1 IT 9021063A1
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- compound according
- aids virus
- properties against
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- 230000015572 biosynthetic process Effects 0.000 title description 6
- 230000000694 effects Effects 0.000 title description 5
- 230000036436 anti-hiv Effects 0.000 title description 4
- OYJGEOAXBALSMM-UHFFFAOYSA-N 2,3-dihydro-1,3-thiazole Chemical compound C1NC=CS1 OYJGEOAXBALSMM-UHFFFAOYSA-N 0.000 title description 3
- 238000003786 synthesis reaction Methods 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 21
- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 11
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- 241000725303 Human immunodeficiency virus Species 0.000 claims description 9
- 230000000840 anti-viral effect Effects 0.000 claims description 9
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 3
- 238000009835 boiling Methods 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 150000003935 benzaldehydes Chemical class 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 150000001556 benzimidazoles Chemical class 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- -1 1H, 3H-Thiazole 1-substituted Benzimidazoles Chemical class 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000002259 anti human immunodeficiency virus agent Substances 0.000 description 1
- 229940124411 anti-hiv antiviral agent Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000000120 cytopathologic effect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 150000002634 lipophilic molecules Chemical class 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 150000004986 phenylenediamines Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000004238 reversed phase thin layer chromatography Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Communicable Diseases (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Virology (AREA)
- Oncology (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Description
Descrizione dell'invenzione industriale dal titolo: Sintesi ed attività anti-HIV di lH,3H-Tiazolo Benzimidazoli 1-sostituiti. Description of the industrial invention entitled: Synthesis and anti-HIV activity of 1H, 3H-Thiazole 1-substituted Benzimidazoles.
La presente invenzione riguarda nuovi composti della classe IH, 3H-tiazolo [3.4-a] benzimidazolo 1-sostituito aventi proprietà antivirali in particolare nei confronti del virus dell'AIDS. La richiesta di individuare nuovi farmaci efficaci nel trattamento dell'AIDS è largamente sostenuta dalla scarsa efficacia terapeutica dei pochi agenti anti-HIV finora disponibili. The present invention relates to new compounds of class IH, 3H-thiazole [3.4-a] 1-substituted benzimidazole having antiviral properties in particular towards the AIDS virus. The demand to identify new drugs effective in the treatment of AIDS is largely supported by the poor therapeutic efficacy of the few anti-HIV agents available so far.
Gli lH,3H-tiazolo [3,4-a] benzimidazoli qui descritti sono stati selezionati dal National Cancer Institute di Bethesda (USA) per la valutazione dell'attività anti-HIV in vitro. The 1H, 3H-thiazole [3,4-a] benzimidazoles described here were selected by the National Cancer Institute of Bethesda (USA) for the evaluation of anti-HIV activity in vitro.
I composti secondo il trovato sono rappresentati dalla formula generale: The compounds according to the invention are represented by the general formula:
A) TO)
dove R3. R4, R5 ed R6 sono scelti tra H, F, Cl.Br.OH, OCH3,CH3,CF3, CN,N02 uno almeno essendo diverso da H. where R3. R4, R5 and R6 are selected from H, F, Cl.Br.OH, OCH3, CH3, CF3, CN, N02 at least one being different from H.
In particolare composti ad attività antivirale nei confronti del virus dell'AIDS sono i seguenti: In particular, compounds with antiviral activity against the AIDS virus are the following:
L'invenzione riguarda pure un procedimento per la preparazione dei composti della formula generale suddetta mediante reazione di o.fenilendiammina con acido 2-mercaptoacetico e con una benzaldeide avente uno o più sostituenti nelle posizioni 2, 3. The invention also relates to a process for the preparation of the compounds of the above general formula by reaction of o.phenylenediamine with 2-mercaptoacetic acid and with a benzaldehyde having one or more substituents in positions 2, 3.
4, 5 o 6. 4, 5 or 6.
La reazione può essere schematizzata nel modo seguente: The reaction can be schematized as follows:
Il meccanismo della reazione come già riportato per composti analoghi in Synthesis (J. of Synthetic Organic Chemistry) (1988) n. 3 marzo pp. 244-246, si basa probabilmente nella formazione anzitutto dell'immino derivato: The mechanism of the reaction as already reported for analogous compounds in Synthesis (J. of Synthetic Organic Chemistry) (1988) n. 3 March pp. 244-246, is probably based on the formation first of all of the imino derivative:
che, per reazione con l'acido 2-mercaptoacetico dà luogo all'intermedio tiazolidinone; which, upon reaction with 2-mercaptoacetic acid, gives rise to the intermediate thiazolidinone;
che ciclizza facilmente eliminando H2O which easily cyclizes eliminating H2O
La formazione di sottoprodotti dovuti alla formazione nel primo stadio di derivati bis-azometinici The formation of by-products due to the formation in the first stage of bis-azomethine derivatives
con conseguente abbassamento della resa del prodotto finale desiderato, viene ridotta con una scelta opportuna della durata della reazione e dei rapporti dei reagenti. with consequent lowering of the yield of the desired final product, it is reduced with a suitable choice of the duration of the reaction and of the reagent ratios.
La reazione viene condotta in un solo stadio usando come solvente di reazione il benzene alla temperatura di ebollizione della soluzione (c.a. 80°C). The reaction is carried out in a single step using benzene as the reaction solvent at the boiling temperature of the solution (about 80 ° C).
L' acido 2 mercapto-acetico viene usato in eccesso. 2 mercaptoacetic acid is used in excess.
Il procedimento rappresenta una valida alternativa ai metodi noti basati nell'impiego di benzimidazoli sostituiti come materiali di partenza e di adatti composti contenenti zolfo per realizzare la ciclizzazione tiazolica. I prodotti di partenza nel processo secondo il trovato sono infatti facilmente disponibili in commercio e non sono costosi. The process represents a valid alternative to the known methods based on the use of substituted benzimidazoles as starting materials and of suitable compounds containing sulfur to carry out the thiazolic cyclization. The starting products in the process according to the invention are in fact readily available on the market and are not expensive.
Condizioni operative generali General operating conditions
Ad una soluzione di 50 mmoli di o-fenilendiamina in 100 mi di benzene anidro, si addizionano 50 mmoli della adatta aldeide e 100 mmoli di acido mercaptoacetico. To a solution of 50 mmoles of o-phenylenediamine in 100 ml of anhydrous benzene, 50 mmoles of the suitable aldehyde and 100 mmoles of mercaptoacetic acid are added.
La miscela di reazione viene poi riscaldata a riflusso per tempi variabili (vedi tab.1). A reazione ultimata, l'intera miscela viene lavata ripetutamente con soluzioni di N 2CO3 al 2%, per allontanare l'acido in eccesso. Distillato il solvente a pressione ridotta, si ottiene un residuo oleoso che abitualmente viene cristallizzato da etere etilico o purificato per via cromatografica. The reaction mixture is then heated under reflux for variable times (see table 1). When the reaction is complete, the entire mixture is repeatedly washed with 2% N 2CO3 solutions, to remove the excess acid. Once the solvent is distilled under reduced pressure, an oily residue is obtained which is usually crystallized from ethyl ether or purified by chromatography.
Il procedimento rappresenta una valida alternativa ai metodi noti basati nell'impiego di benzimidazoli sostituiti come materiali di partenza e di adatti composti contenenti zolfo per realizzare la ciclizzazione tiazolica. 1 prodotti di partenza nel processo secondo il trovato sono infatti facilmente disponibili in commercio e non sono costosi. The process represents a valid alternative to the known methods based on the use of substituted benzimidazoles as starting materials and of suitable compounds containing sulfur to carry out the thiazolic cyclization. The starting products in the process according to the invention are in fact readily available on the market and are not expensive.
Metodi adottati per l'analisi dei prodotti e la determinazione delle loro caratteristiche chimico-fisiche. Methods adopted for the analysis of the products and the determination of their chemical-physical characteristics.
I punti di fusione sono stati determinati con un apparecchio di Kofler e non sono corretti. The melting points were determined with a Kofler apparatus and are not correct.
Le analisi elementari sono state eseguite con un Elemental Analyzer Carlo Erba mod. 1106 e i valori trovati sono risultati compresi nell'intervallo ± 0 dei valori teorici. The elementary analyzes were performed with an Elemental Analyzer Carlo Erba mod. 1106 and the values found were within the ± 0 range of the theoretical values.
II decorso delle reazioni e la purezza dei composti sono stati controllati mediante cromatografia su strato sottile (Kieselgel 60 254 Merck) usando come eluente una miscela etere etilico/etere di petrolio (8:2). The course of the reactions and the purity of the compounds were checked by thin layer chromatography (Kieselgel 60 254 Merck) using a mixture of ethyl ether / petroleum ether (8: 2) as eluent.
Gli spettri Ή-R.M.N. sono stati registrati con uno spettometro Bruker WP 80 SY. I Chemical shifts sono espressi in δ (ppm) e le costanti di accoppiamento (J) in Hz. The spectra Ή-R.M.N. were recorded with a Bruker WP 80 SY spectometer. Chemical shifts are expressed in δ (ppm) and the coupling constants (J) in Hz.
Gli spettri di tutti i composti sono stati registrati in soluzione di CDCl3 o di DMS0-d6. Spectra of all compounds were recorded in CDCl3 or DMS0-d6 solution.
Le caratteristiche chimiche e fisiche di alcuni dei prodotti sintetizzati sono state riassunte nella tab. I e le relative strutture sono in accordo sia con i dati analitici elementari che con quelli spettroscopici. The chemical and physical characteristics of some of the synthesized products have been summarized in tab. I and related structures are in agreement with both elementary and spectroscopic analytical data.
MISURE DI LIPOFILIA MEASURES OF LIPOPHILIA
Il carattere lipofilo dei composti sintetizzati è stato valutato mediante cromatografia su strato sottile in fase inversa. The lipophilic character of the synthesized compounds was evaluated by reversed phase thin layer chromatography.
La fase stazionaria non polare è rappresentata da lastre di gel di silice silanizzate Merck 60 254 mentre la fase polare è costituita da una miscela acetone/acqua (2:1). The non-polar stationary phase is represented by Merck 60 254 silanized silica gel plates while the polar phase consists of an acetone / water mixture (2: 1).
I composti sono stati solubilizzati in cloroformio (3mg/ml)· I valori di RM sono stati calcolati dai valori sperimentali medi di RF, ottenuti da tre cromatogrammi, applicando la formula: The compounds were solubilized in chloroform (3mg / ml) The RM values were calculated from the experimental mean values of RF, obtained from three chromatograms, applying the formula:
Valori di RM più alti, corrispondenti ai più bassi valori di Rp, indicano composti più lipofili. Higher RM values, corresponding to lower Rp values, indicate more lipophilic compounds.
La relativa lipofilia (RM) dei prodotti sintetizzati è riportata nella tabella 1. The relative lipophilicity (RM) of the synthesized products is shown in Table 1.
Le modalità, le condizioni di esecuzione dei tests, i criteri di valutazione dell'attività anti-HIV in vitro sono descritti da Weislow, O.W., Kiser, R., Fine, D., Bader, J., Shoemaker, R.H. , Boyd, M.R.: New soluble-formazan assay for HIV-1 cytopathic effects: application to high-flux screening of synthetic and naturai products for AIDS-antiviral activity. J. Nati. Cancer Inst. 81:577-586,1989. The methods, the conditions of execution of the tests, the evaluation criteria of the anti-HIV activity in vitro are described by Weislow, O.W., Kiser, R., Fine, D., Bader, J., Shoemaker, R.H. , Boyd, M.R .: New soluble-formazan assay for HIV-1 cytopathic effects: application to high-flux screening of synthetic and naturai products for AIDS-antiviral activity. J. Nati. Cancer Inst. 81: 577-586,1989.
I risultati del test per i composti IV, V, XVII, XXII, XXVI, XXIX e XXX sono riportati nei diagrammi delle figure da 1 a 7 rispettivamente e nelle tabelle da 2 a 8 qui nel seguito. The test results for compounds IV, V, XVII, XXII, XXVI, XXIX and XXX are shown in the diagrams of Figures 1 to 7 respectively and in Tables 2 to 8 below.
Gli esempi riportati illustrano ma non limitano la presente invenzione . The examples given illustrate but do not limit the present invention.
Claims (2)
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT02106390A IT1243362B (en) | 1990-07-25 | 1990-07-25 | SUMMARY OF ANTI-HIV ACTIVITY OF 1H, 3H-THIAZOLE 3,4-A BENZIMIDAZOLE 1-SUBSTITUTED |
| EP19910112224 EP0471991A3 (en) | 1990-07-25 | 1991-07-22 | 1-phenyl substituted 1h,3h-thiazolo(3,4-a)benzimidazoles, process for their preparation, and pharmaceutical compositions containing them |
| CA002047796A CA2047796A1 (en) | 1990-07-25 | 1991-07-24 | 1-phenyl substituted-1h, 3h-thiazole [3,4-a] benimidazoles, process for their preparation and pharmaceutical compositions containing them |
| JP3207158A JPH04234395A (en) | 1990-07-25 | 1991-07-25 | New 1-phenyl-substituted 1h, 3h-thiazole- (3,4-a)benzimidazoles, process for preparing same and medicinal compositions containing same |
| US07/735,914 US5217984A (en) | 1990-07-25 | 1991-07-25 | 1-phenyl substituted-1H, 3H-thiazole [3,4-a] benzimidazoles and pharmaceutical compositions containing them |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT02106390A IT1243362B (en) | 1990-07-25 | 1990-07-25 | SUMMARY OF ANTI-HIV ACTIVITY OF 1H, 3H-THIAZOLE 3,4-A BENZIMIDAZOLE 1-SUBSTITUTED |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| IT9021063A0 IT9021063A0 (en) | 1990-07-25 |
| IT9021063A1 true IT9021063A1 (en) | 1992-01-25 |
| IT1243362B IT1243362B (en) | 1994-06-10 |
Family
ID=11176175
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IT02106390A IT1243362B (en) | 1990-07-25 | 1990-07-25 | SUMMARY OF ANTI-HIV ACTIVITY OF 1H, 3H-THIAZOLE 3,4-A BENZIMIDAZOLE 1-SUBSTITUTED |
Country Status (5)
| Country | Link |
|---|---|
| US (1) | US5217984A (en) |
| EP (1) | EP0471991A3 (en) |
| JP (1) | JPH04234395A (en) |
| CA (1) | CA2047796A1 (en) |
| IT (1) | IT1243362B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU741772B2 (en) | 1997-02-25 | 2001-12-06 | Government Of The United States Of America, As Represented By The Secretary Of The Department Of Health And Human Services, The | Substituted benzimidazoles as non-nucleoside inhibitors of reverse transcriptase |
| US20060040111A1 (en) * | 2004-08-20 | 2006-02-23 | Dolechek Kert L | Process chamber and system for thinning a semiconductor workpiece |
| DE102009038123A1 (en) | 2009-08-17 | 2011-02-24 | Aicuris Gmbh & Co. Kg | Substituted (thiazolyl-carbonyl) imidazolidinones and their use |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3665007A (en) * | 1970-05-04 | 1972-05-23 | Squibb & Sons Inc | Thiazolo (3,4-a) benzimidazoles and derivatives thereof |
| US3732240A (en) * | 1971-01-21 | 1973-05-08 | Squibb & Sons Inc | Thiazolo(3,4-a)benzimidazole derivatives and process |
| FR2463774A1 (en) * | 1979-08-21 | 1981-02-27 | Yamanouchi Pharma Co Ltd | DERIVATIVES OF 2-PHENYLIMIDAZO (2,1-B) BENZOTHIAZOLE |
| US4464384A (en) * | 1981-12-23 | 1984-08-07 | Yamanouchi Pharmaceutical Co., Ltd. | 2-Phenylimidazo[2,1-b]benzothiazole compounds, salts thereof, process of producing them, and pharmaceutical compositions containing them |
| GB8701228D0 (en) * | 1987-01-21 | 1987-02-25 | Wyeth John & Brother Ltd | Thiazolobenzimidazoles |
-
1990
- 1990-07-25 IT IT02106390A patent/IT1243362B/en active IP Right Grant
-
1991
- 1991-07-22 EP EP19910112224 patent/EP0471991A3/en not_active Withdrawn
- 1991-07-24 CA CA002047796A patent/CA2047796A1/en not_active Abandoned
- 1991-07-25 JP JP3207158A patent/JPH04234395A/en active Pending
- 1991-07-25 US US07/735,914 patent/US5217984A/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CA2047796A1 (en) | 1992-01-26 |
| IT1243362B (en) | 1994-06-10 |
| IT9021063A0 (en) | 1990-07-25 |
| JPH04234395A (en) | 1992-08-24 |
| EP0471991A2 (en) | 1992-02-26 |
| EP0471991A3 (en) | 1992-03-11 |
| US5217984A (en) | 1993-06-08 |
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